The extracellular volume status predicts body fluid response to SGLT2 inhibitor dapagliflozin in diabetic kidney disease

Ken Ohara, Takahiro Masuda, Masato Morinari, Mari Okada, Atsushi Miki, Saki Nakagawa, Takuya Murakami, Kentaro Oka, Maki Asakura, Yasuharu Miyazawa, Akito Maeshima, Tetsu Akimoto, Osamu Saito, Daisuke Nagata, Ken Ohara, Takahiro Masuda, Masato Morinari, Mari Okada, Atsushi Miki, Saki Nakagawa, Takuya Murakami, Kentaro Oka, Maki Asakura, Yasuharu Miyazawa, Akito Maeshima, Tetsu Akimoto, Osamu Saito, Daisuke Nagata

Abstract

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an antihyperglycemic drug with diuretic action. We recently reported that the SGLT2 inhibitor dapagliflozin ameliorates extracellular volume expansion with a mild increase in urine volume. However, the impact of the pretreatment extracellular volume status on the body fluid response to SGLT2 inhibitors remains unclear.

Methods: Thirty-six diabetic kidney disease (DKD) patients were treated with dapagliflozin. The body fluid volume, including intracellular water (ICW), extracellular water (ECW) and total body water (TBW), were measured on baseline and day 7 using a bioimpedance analysis (BIA) device. The ECW/TBW and ECW were used as markers of the extracellular volume status. For a comparison, the extracellular volume status responses to loop diuretic furosemide (n = 16) and vasopressin V2 receptor antagonist tolvaptan (n = 13) were analyzed.

Results: The body weight, brain natriuretic peptide and body fluid parameters measured by a BIA (ICW, ECW, TBW, and ECW/TBW) were significantly decreased for 1 week after dapagliflozin administration. The change in the ECW/TBW in the high-ECW/TBW group (over the median value of 0.413) was significantly higher than in the low-ECW/TBW group (- 2.1 ± 0.4 vs. - 0.5 ± 0.4%, p = 0.006). Only with dapagliflozin treatment (not furosemide or tolvaptan treatment) was the baseline ECW/TBW significantly correlated with the changes in the ECW/TBW (r = - 0.590, p < 0.001) and ECW (r = - 0.374, p = 0.025).

Conclusions: The pretreatment extracellular volume status predicts the body fluid response to the SGLT2 inhibitor dapagliflozin in DKD patients. The diminished extracellular fluid reduction effect of dapagliflozin in patients without severe extracellular fluid retention may contribute to maintaining a suitable body fluid status.

Keywords: BNP; Bioimpedance analysis; Extracellular volume expansion; Furosemide; Heart failure; Hypovolemia; Loop diuretic; SGLT2 inhibition; Tolvaptan; Vasopressin V2 receptor antagonist.

Conflict of interest statement

Competing interestsThe authors declare that they have no competing interests.

© The Author(s) 2020.

Figures

Fig. 1
Fig. 1
Absolute changes in the ECW/TBW depending on high vs. low ECW/TBW and the BNP at baseline. a The absolute change in the high-ECW/TBW group (over the median value of 0.413, n = 18) were significantly higher than those in the low-ECW/TBW group (less than the median value of 0.413, n = 18). b The absolute change in the high-BNP group (over the median value of 95.7 pg/mL, n = 14) were significantly higher than those in the low-BNP group (less than the median value of 95.7 pg/mL, n = 13). ECW extracellular water, TBW total body water. *p < 0.05 vs. low-ECW/TBW group or low-BNP group
Fig. 2
Fig. 2
The correlation between baseline ECW/TBW and the absolute change in ECW/TBW. In the furosemide (a) and tolvaptan (c) groups, the ECW/TBW level was not significantly correlated, while in the Dapagliflozin group (b), it was negatively and significantly correlated. ECW extracellular water, TBW total body water
Fig. 3
Fig. 3
The correlation between baseline ECW/TBW and the change in ECW. In the furosemide (a) and tolvaptan (c) groups, the ECW/TBW level was not significantly correlated, while in the Dapagliflozin group (b), it was negatively and significantly correlated. ECW extracellular water, TBW total body water

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